Increasing dosage even by factor of four to five did not prevent exacerbations

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Escalating inhaled steroid dosages to five times the normal dose early in an asthma flare-up failed to prevent exacerbations or minimize their severity in a study of children with mild-to-moderate persistent asthma.

Note that in a separate study involving teens and adults, quadruple doses of inhaled glucocorticoids did result in fewer exacerbations, but it was not clear if the difference was clinically meaningful.

ORLANDO -- Escalating inhaled steroid dosages to five times the normal dose early in an asthma flare-up failed to prevent exacerbations or minimize their severity in a study of children with mild-to-moderate persistent asthma, researchers reported here.

In a separate study involving teens and adults, quadruple doses of inhaled glucocorticoids did result in fewer exacerbations, but it was not clear if the difference was clinically meaningful.

The two studies examined the common strategy of escalating inhaled glucocorticoids during so called "yellow-zone" period when asthma control has just begun to deteriorate.

Both studies were reported Saturday at the joint meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the World Allergy Organization (WAO), in conjunction with their publication in The New England Journal of Medicine.

Daniel J. Jackson, MD, of the University of Wisconsin School of Medicine-Madison, said that based on the new findings, policy makers and clinicians should revisit the common practice of giving inhaled steroids at greatly escalated doses at the first signs of asthma flare-up.

"We found that it really wasn't beneficial to quintuple the dose in these children who were already taking inhaled steroids regularly," he told MedPage Today.

Initiating very aggressive treatment in the early period of failing asthma control, known as the "yellow zone," is a common treatment strategy designed to prevent full-blown exacerbations or lessen their severity. But the evidence of its effectiveness is inconclusive, at best.

A Cochrane Review of studies involving children and adults with asthma, published in 2016, found that "current evidence does not support" increasing inhaled steroid doses early in an asthma attack to lessen its severity. Most of the studies included in the review compared usual dosing to double the usual dosage, however.

The two newly reported studies are among the first large trials to examine much larger inhaled glucocorticoid doses.

The pediatric study included 254 children between the ages of 5 and 11 who had experienced at least one asthma exacerbation treated with systemic glucocorticoids during the previous year.

All received maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) during the 48-week trial, with half assigned to the escalated dose for 7 days at the early signs of loss of asthma control (220 μg per inhalation, two inhalations twice daily).

Treatment was double-blind, and the primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between the two groups.

Specifically:

There were 0.48 exacerbations per year in the high-dose children and 0.37 exacerbations per year in the low-dose group (relative rate, 1.3, 95% CI, 0.8-2.1; P=0.30)

Time to first exacerbation, treatment failure rate, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between the two groups

Total glucocorticoid exposure was 16% higher in the high-dose group, and the difference in linear growth between the high- and low-dose children was -0.23 cm per year (P=0.06)

The second study, in adolescents and adults, included 1,922 asthma patients age 16 or older taking inhaled glucocorticosteroid with or without add-on medications. All participants had experienced at least one exacerbation leading to systemic steroid treatment during the previous year.

Timothy Harrison, MD, of the University of Nottingham in the U.K., and colleagues, compared a self-management plan of increasing the dose of inhaled glucocorticoids by a factor of four with usual dosing early in loss of asthma control.

Among the main findings:

45% of the quadrupling group and 52% of the usual dosage group had a severe asthma exacerbation in the year following randomization (adjusted HR for time to exacerbation, 0.81, 95% CI, 0.71-0.92; P=0.002)

The rate of adverse effects, primarily related to the local effects of the inhaled steroids, was higher in the quadrupling group

In an editorial published with the two studies, Philip G. Bardin, PhD, of Monash University in Melbourne, Australia, noted that the 19% reduction in exacerbation incidence recorded in the trial was lower than the 30% reduction postulated by Harrison and colleagues as a worthwhile treatment effect.

Bardin also pointed out that the majority of participants (70%) took inhaled steroids with long-acting beta-agonists as maintenance therapy, which may have reduced exacerbation reporting.

"Currently, clinicians are challenged to prevent and treat asthma exacerbation and to implement self-management plans," he concluded. "Evidence indicates that substantial escalation of regularly used inhaled glucocorticoids, even by a factor of four or five, fails to prevent most asthma exacerbations. A small subgroup of adults and adolescent with asthma may have a response to an escalation strategy; however, their baseline and exacerbation characteristics remain to be defined."

Funding for the study by Jackson et al was provided by the National Heart, Lung and Blood Institutes.

Funding for the study by Harrison et al was provided by the Health Technology Assessment Programme of the National Institute for Health Research.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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